ABSTRACT STAT3 is an oncogenic transcription factor that is hyperactivated in many cancers, contributing to growth, survival and therapeutic resistance. The mechanisms mediating increased STAT3 activation in human cancers are incompletely understood. Head and neck squamous cell carcinoma (HNSCC) is a leading cause of cancer mortality worldwide. We previously reported increased STAT3 activation in HNSCC associated with treatment resistance. Previous reports indicate that protein tyrosine receptor phosphatases T (PTPRT) and D (PTPRD) negatively regulate STAT3 activation. We determined the mutational profile of HNSCC, and detected mutations in the PTPR family in nearly one-third of the cases analyzed. Studies proposed here will test the hypothesis that aberrant STAT3 activation results from PTPR mutations, and that STAT3 is a key therapeutic target in cancers harboring these mutations. We have developed a STAT3-selective decoy that inhibits STAT3 target gene expression in HNSCC tumors treated on a recently completed phase 0 trial. In addition, preliminary evidence indicates that the JAK/STAT inhibitor AZD1480 abrogates STAT3 activation and HNSCC growth. We propose to determine whether tumors that harbor PTPR mutations demonstrate enhanced sensitivity to STAT3 inhibition using relevant preclinical HNSCC models and our unique access to tumors from HNSCC patients enrolled in a presurgical trial of a small molecule JAK/STAT inhibitor.